Regulation of postnatal hypothalamic neurogenesis by fibroblast growth factor (FGF) signalling

Kaminskas, Benediktas (2018) Regulation of postnatal hypothalamic neurogenesis by fibroblast growth factor (FGF) signalling. Doctoral thesis, University of East Anglia.

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The hypothalamus is crucial for maintaining homeostasis. It regulates energy balance, circadian rhythms and other processes through the activity of neuronal nuclei and specialised cells lining the third ventricle wall called tanycytes. Hypothalamic tanycytes are candidate neural stem/progenitor cells that give rise to neurons in appetite-regulating nuclei in adult hypothalamus. The fibroblast growth factor (FGF) system is emerging as an important regulator of hypothalamic neurogenesis and metabolism. However, the endogenous FGF/FGFR signalling partners in tanycytes and their exact functions remain unknown. In this study, three approaches were taken to address this. First, the expression of FGF ligands, receptors and signalling
modulators in the hypothalamus were examined by using RT-PCR, in situ hybridization, immunohistochemistry and reporter mice. FGF receptors were found to be restricted to the β-tanycyte domain and multiple cognate FGF ligands were also expressed by tanycytes. Second, the in vivo function of FGF receptors in postnatal hypothalamic neurogenesis was assessed by conditionally deleting Fgfr1 and Fgfr2 in Fgf10+ β-tanycytes and subsequent lineage tracing of these cells. This resulted in amplification of lineage traced cells, revealing a role for FGFR signalling in regulating the number of tanycytes and neurons generated in postnatal hypothalamus, likely by inhibiting proliferation. Recent reports showed that modulation of FGFR signalling in mediobasal hypothalamus, including tanycytes, results in hypophagia and greatly improved glucose homeostasis. Here, the metabolic functions of Fgfr1 and Fgfr2 were assessed by conditional deletion in β-tanycytes of lean and diet-induced-obese mice. Subtle effects on weight and glucose metabolism were observed, suggesting that endogenous FGFR signalling in tanycytes may not play a major role in regulating metabolism. Third, RNA-seq identified a downregulation of the orexigenic neuropeptide Agrp in FGF10 KO embryonic hypothalamus. Here, the importance of FGFR-independent FGF10 signalling for regulating Agrp expression and the potential molecular mechanisms were confirmed by in situ hybridization.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Zoe White
Date Deposited: 19 Jun 2019 12:57
Last Modified: 18 Oct 2021 12:23

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